title: Innate sensing of HIV-infected cells.
abstract: Cell-free HIV-1 virions are poor stimulators of type I interferon (IFN) production. We examined here how HIV-infected cells are recognized by plasmacytoid dendritic cells (pDCs) and by other cells. We show that infected lymphocytes are more potent inducers of IFN than virions. There are target cell-type differences in the recognition of infected lymphocytes. In primary pDCs and pDC-like cells, recognition occurs in large part through TLR7, as demonstrated by the use of inhibitors and by TLR7 silencing. Donor cells expressing replication-defective viruses, carrying mutated reverse transcriptase, integrase or nucleocapsid proteins induced IFN production by target cells as potently as wild-type virus. In contrast, Env-deleted or fusion defective HIV-1 mutants were less efficient, suggesting that in addition to TLR7, cytoplasmic cellular sensors may also mediate sensing of infected cells. Furthermore, in a model of TLR7-negative cells, we demonstrate that the IRF3 pathway, through a process requiring access of incoming viral material to the cytoplasm, allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs through both endosomal and cytoplasmic pathways. Characterization of the mechanisms of innate recognition of HIV-infected cells allows a better understanding of the pathogenic and exacerbated immunologic events associated with HIV infection.
authors.affiliation: Institut Pasteur, Virus and Immunity Unit, URA CNRS 3015, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Lepelley
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Louis
authors.forename: Marion
authors.initials: M
authors.lastname: Sourisseau
authors.forename: Helen K W
authors.initials: HK
authors.lastname: Law
authors.forename: Julien
authors.initials: J
authors.lastname: Pothlichet
authors.forename: Clémentine
authors.initials: C
authors.lastname: Schilte
authors.forename: Laurence
authors.initials: L
authors.lastname: Chaperot
authors.forename: Joël
authors.initials: J
authors.lastname: Plumas
authors.forename: Richard E
authors.initials: RE
authors.lastname: Randall
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mammano
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
authors.forename: Olivier
authors.initials: O
authors.lastname: Schwartz
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006678:HIV; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D006679:HIV Seropositivity; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000472:pathogenicity; D014779:Virus Replication
chemical_list: D006023:Glycoproteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D012333:RNA, Messenger; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7